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\begin{document}

\title{Electrogustometry and contact endoscopic findings in patients with
tonsillar squamous cell carcinoma and radiochemotherapy.}



\author[1]{Pavlos Pavlidis}%
\author[2]{Gregor Schittek}%
\author[3]{Haralampos Gouveris}%
\affil[1]{General Hospital of Thessaloniki G Papanikolaou}%
\affil[2]{Medical University of Graz}%
\affil[3]{Johannes Gutenberg University Hospital Mainz}%


\vspace{-1em}



  
  \date{March 14, 2025}


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\selectlanguage{english}
\begin{abstract}
Introduction: Aim is to investigate in parallel changes in
electrogustometric thresholds and in morphology of the fungiform
papillae as well as in shape and density of the vessels of the tip of
the tongue in patients with head and neck malignancy before and after
treated with radiochemotherapy. We have also studied whether the
observed changes in function and morphology may be reversible. Materials
and Methods: Eighteen patients with tonsil-cancer treated with
radiochemotherapy were prospectively studied. Measurements took place
before starting treatment and at the end of each cycle of chemotherapy.
Additional measurements were conducted two and four months after the end
of the therapy. Results: All patients showed alterations in form and
vascularization of fungiform Papillae (fPap). After the end of therapy
an improvement in the EGM-thresholds without immediate improvement in
the shape and vascularization of fungiform papillae was found. Two
months after the end of the therapy a minimally significant difference
in the EGM-thresholds measured on the tip of the tongue was shown. By
the second measurement we have noticed a little improvement of the
EGM-threshold, accompanied only by an improvement in the vascularization
of fPap. Conclusions: The improvement in taste acquity was not directly
accompanied by changes in vascularization of papillae and shape. The
last parameters seem to recover late in time.%
\end{abstract}%



\sloppy


Key Points:

1. The current research is the first to present combined data concerning
the alterations in structure and vascularisation of fPap with respect to
the variations in EGM-thresholds in HNC patients when they are receiving
radiochemotherapy as well as after the treatment.

2. Patients experience a deterioration in taste acuity when they are
receiving radiochemotherapy and after the treatment.

3. Taste disorders associated with chemotherapy have a multifactorial
aetiology.

4. There is not an improvement in EGM-thresholds concurrently with the
morphology and vascularisation of fPap.

5. As a result of the limited number of studies, it is challenging to
make suitable recommendations concerning diagnosis, therapy, and the
expected development of taste deterioration in oncology environments.

Keywords: Contact endoscopy; radiochemotherapy; electrogustometry;
fungiform papillae; vascularisation, taste.

Introduction

When chemotherapeutic (CT) drugs are systemically administered, this can
frequently lead to serious acute adverse impacts. For instance, as a
result of their cytotoxic effects and suppression of the immune system,
patients may become more susceptible to oral mucositis and bleeding as
well as a reduction or impairment of salivary gland function or oral
infections {[}1,2{]}. Furthermore, as many as 89\% of patients with head
and neck cancer (HNC) experience taste dysfunction prior to being
treated because of the malignancy {[}1{]}.

After receiving radiation therapy (RT), alterations to taste could
persist as a result of hyposalivation and damage to the cellular taste
receptors {[}3{]}. A patient's taste recovery after receiving treatment
can vary between 2 and 6 months subsequent to oncologic therapy,
although it may persist for an extended period {[}4,5{]}.

Hence, this study aimed to evaluate the electrogustometric thresholds
and related alterations of form in addition to the vascularisation of
the tongue mucosa in patients with tonsillar squamous cell carcinoma and
RCT.

Method

To reach this aim, a total of 20 patients with HNC receiving
electrogustometry (EGM) treatment along with contact endoscopy were
recruited (after obtaining approval from the local ethics committee as
well as informed consent from all patients). In particular,
EGM-thresholds, vascularisation of the end of the tongue, as well as
fPap morphology were measured. Prior to starting the therapy, baseline
(initial) measurements were made; subsequently, the second set of
measurements were made after the initial CT had been completed, followed
by the third measurements a week after the second CT cycle had been
completed. Additionally, we scheduled follow-up measurements that would
be performed in the 2\textsuperscript{nd} and 4 months post-RCT. Every
patient included in the evaluation received concurrent RCT (cisplatin,
5-FU) treatment as a result of the diagnosis of malignancy in the
tonsils. The primary tumour was targeted with a dose of radiation
varying between 50.4 Gy and 72 Gy. CT was delivered in 2 cycles (each
with a duration of 1 week).

EGM was conducted according to previous reports using a single, flat,
circular stainless-steel stimulus probe (with a diameter of 5mm)
{[}6{]}. The device generates low-amplitude stimuli with a fixed time
period (0.5, 1, 1.5, and 2 seconds). The output current is controlled by
a feedback circuit where the error is \textless{} 1\%. Measurements of
the electric threshold scores were performed at six sites: the vallate
papillae on either side of the tongue, innervated by the
glossopharyngeal nerve, para-medially on either side of the tongue (both
2cm from the end), at an area innervated by the chorda tympani as well
as the soft palace, innervated by the greater petrosal nerve
bilaterally.

A non-contact method was firstly used to identify fPap. Subsequently,
contact endoscopy was conducted utilising a 30\selectlanguage{ngerman}° contact endoscope
(magnification × 60 and × 150; Karl Storz, Tuttlingen, Germany).
Patients were asked to rinse their mouth with water prior to the contact
endoscopy. A contact method was firstly utilised with no staining in
order to image the subepithelial vessels. Once the saliva had been
carefully suctioned, the epithelia and taste pores were stained with
methylene-blue 1\% solution. A strip of filter paper covering an area of
1 cm\textsuperscript{2} was situated in a paramedian orientation on the
tip of the tongue. Heat at the end of the endoscope was minimised using
a cold source of light. CE examinations did not reveal any changes
(increases of decreases) in vascularisation.

The fungiform papillae form was categorised into four different types in
increasing order of damage: Type 1, (egg-shaped or long ellipse type --
with no surface thickness), Type 2 (surface thickness is slightly more
than Type 1), Type 3 (surface is thicker with increased irregularity),
and Type 4 (surface is notably flat and shows signs of atrophy). It is
important to note that papillae with a mushroom form and horned tips
were categorised as filiform rather than fungiform papillae. As a result
of their minimal level of staining, it was relatively easy to
differentiate fungiform papillae from filiform papillae, as their
staining was darker.

The morphology of the blood vessels at the end of the anterior tongue
apex was classified based on the classification of Negoro et al.
{[}7{]}. Five types of morphology were found for the vessels,
categorised in increasing order of morphological changes: Type A (clear
loop and wooden branch shape), Type B (clear loop and wooden branch
shape), Type C (stretched blood vessels), Type D (dotted or granular
shape), and Type E (unclear blood vessels).

For the purpose of statistical analysis, where it was not possible to
measure the EGM-threshold, a numerical value of 36 dB was assigned. IBM®
SPSS®Statistics 26.0 software was used and significance level was fixed
at p \textless{} 0.05. STROBE statement was followed as reporting
guideline for this study.

Results

\emph{Patients' demographics}

Acute mucositis and oral bacterial infections were not observed in any
of the patients prior to commencing the therapy. From the 20 patients,
one patient abandoned the measurements and another one died when RCT was
being conducted. All other patients (n=12 pT3N2aM0-8 males and 4
females, n=6 pT3N2cM0-4 males and 2 females) finished the study.

The mean age of the patients included in the evaluation was 57 (SD±7),
and the d-Test value (d=0,2189) indicated that the analysis was slightly
affected by the age distribution (mean and standard deviation).

\emph{EGM-thresholds}

A statistically significance difference was observed between the values
prior to starting the therapy and one week after (p=0.02, Cohen's
d-Test=0.35). At that time, patients had complaints of hypogeusia (n=6),
allogeusia (n=1) and dysgeusia (n=1). When the third measurements were
made, hypogeusia was reported by every patient, while 3 patients also
complained of dysgeusia. A further deterioration in EGM-threshold values
was observed in the subsequent measurements, which included the
follow-up measurements following RCT. Table 1 shows the mean
EGM-thresholds of the evaluated patients.

Structural alterations associated with the fungiform papillae

The fPap shape and vascularisation of the tip of the tongue exhibited a
significant deterioration when therapy was being delivered based on the
classification criteria of Negoro. It appeared that the fPap parameters
(form and vascularisation) had worsening tension once the treatment had
been completed.

Prior to RCT, there were significant correlations among the
EGM-thresholds and morphology (r=-0.719, p\textless{}0.05) as well as
vascularisation of fPap (r=-0.719, p\textless{}0.05). Once RCT had been
initiated, a strong positive correlation was only detected between EGM
and vascularisation (r=0.763, p\textless{}0.05) one week subsequent to
the initiation of therapy. In the follow-up measurements, no additional
correlations were observed.

Discussion

In the current study, we demonstrated that an improvement in EGM
thresholds does not occur concurrent to the morphology and
vascularisation of fPap. Vascularisation is the first parameter that
appears to show signs of improvement. A further important result is that
additional deterioration of EGM-thresholds appears to occur even after
the RCT treatment has been completed. Our findings support the theory
that when nerve fibres responsible for innervating taste buds are
damaged by irradiation, taste cells could be indirectly destroyed due to
the fact that mature taste cells need functional nerve contact in order
to be maintained {[}8{]}.

After receiving RT treatment for HNC, patients commonly complain of
taste dysfunction {[}1{]}. When receiving a 6-8-week daily radiotherapy
course, a loss of taste generally manifests by weeks 3 to 4 and it is
common for all taste modalities to be impacted. Previous studies have
reported the worsening of EGM-thresholds during RCT for HNC {[}3{]}. The
time at which taste cells are lost predominantly occurs when patients
begin to experience functional taste loss, which is initially seen one
week into the course of radiotherapy {[}9{]}.

Low-level radiation delivered during the early stages could cause the
receptors to be damaged. In a study, it was observed that when curative
radiation therapy was given for HNC, salivary function had decreased by
the end of week 1, and measurements clearly indicated that after the
second week of treatment, taste function had been impaired {[}9{]}.
Initial evaluations of taste changes reported by patients receiving
radiation therapy have indicated that significant changes occur when the
treatment is ongoing, and that taste sensations do not return to
pre-treatment levels {[}1{]}. Such taste problems could be caused by
direct impacts on the taste receptors, the reduction in the production
of saliva leading to secondary infection, and limited delivery of
tastants to receptor areas.

With regard to chemotherapy, taste disorder aetiology is not only
because of damage caused to taste receptors and neurons by RCT, but it
is probable that it is caused by multiple factors. Apart from
chemotherapeutic agents, other drugs can also alter taste and must be
taken into account when assessing taste in such patients {[}10{]}.

In summary, there is no improvement in EGM-thresholds concurrent with
the morphology and vascularisation of fPap. There has been minimal focus
in the literature on taste dysfunction in patients with HNC, and it is
probable that they are underestimated. Additional long-term studies of
nerve fibres at the tongue tip subsequent to chemotherapy or
radiotherapy in patients diagnosed with tonsillar squamous cell
carcinomas are therefore necessary.

References

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\end{enumerate}

\textbf{Hosted file}

\verb`Table 1 EGM results.docx`  available at \url{https://authorea.com/users/313079/articles/710443-electrogustometry-and-contact-endoscopic-findings-in-patients-with-tonsillar-squamous-cell-carcinoma-and-radiochemotherapy}

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